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Principal Investigator: Hu Zeng
Organization: MAYO CLINIC ROCHESTER
Fiscal Year: 2024
Award: $470,828
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Amino acids are crucial nutrients that are also important to support immunity. Yet, we have limited
understanding with regard to how immune challenges modulate amino acid availability, and how immune cells
sense amino acid and transduce the signals to execute immune reponses. Rag-GTPase has recently been
identified as a key amino acid sensor that mostly transduce signals from amino acids to mechanistic target of
rapamycin (mTOR) complex 1 (mTORC1) in non-hematopoietic cells. However, Rag-GTPase also modulates
transcription factor TFEB, a member of the microphthalmia (MiT/TFE) family of HLH-leucine zipper
transcription factors, whose functions in B cells remain unknown. Moreover, Rag-GTPase independent
mTORC1 activation has been identified. How Rag-GTPase and mTORC1 coordinates to regulate humoral
immunity has not been addressed. We compared the functions of Rag-GTPase and mTORC1 in B cell
response in vivo using genetic knockout models. Our data showed that while both Rag-GTPase and mTORC1
are required for systemic immune challenges, Rag-GTPase, but not mTORC1, is critical for humoral immune
response towards respiratory influenza infection. This divergent requirement between Rag-GTPase and
mTORC1 is associated with differential amino acid availability between systemic immunization and airway
influenza infection. Furthermore, we showed that Rag-GTPase suppresses TFEB and promotes autophagy,
which is associated with ERK activation, but largely independent of mTORC1. Thus, we hypothesize that
reduced availability of specific amino acids during respiratory viral infection renders B cells dependent on Rag-
GTPase-TFEB pathway, for GC reaction and anti-influenza antibody production. In Aim 1, we will first test
whether the respiratory route of live virus immune challenge is the determining factor for Rag-GTPase
dependent, but mTORC1 independent, humoral immunity. Second, we will further investigate the temporal and
spatial dynamics of amino acid availability during immune challenges. Finally, we will test whether dietary
amino acid intervention can improve humoral immunity against respiratory viral infection. In Aim 2, we will
utilize complementary loss-of-function and gain-of-function approaches to elucidate the downstream signaling
mechanisms by which Rag-GTPase promotes GC reaction and humoral immunity. We will further characterize
the Rag-GTPase interactome in B cells using unbiased proteomics approach. Our study will define a novel
Rag-GTPase-ERK-TFEB signaling axis that respond to amino acid availability to promote B cell activation and
antibody production against airway viral infection.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Ab response><Address><Allergens><Amino Acids><Antibodies><Antibody Formation><Antibody Production><Antibody Therapy><Autophagocytosis><B blood cells><B cell><B cells><B-Cell Activation><B-Cells><B-Lymphocytes><B-cell><Basal Transcription Factor><Basal transcription factor genes><COVID-19><COVID-19 virus><COVID19 virus><CV-19><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><CoV-2><CoV2><Complex><Coronavirus Infectious Disease 2019><D-Glucose><Data><Development><Dextrose><ERK MAP Kinases><Event><Extracellular Signal Regulated Kinases><Extracellular Signal-Regulated MAP Kinases><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Family><Fatty Acids><GTP Phosphohydrolases><GTPases><General Transcription Factor Gene><General Transcription Factors><Genetic><Germinal Center><Glucose><Guanosine Triphosphate Phosphohydrolases><Guanosinetriphosphatases><Humoral Immunities><IFN><Immune><Immune response><Immunes><Immunity><Immunization><Immunological response><Immunomodulation><In Vitro><Infection><Influenza Virus><Interferons><Intermediary Metabolism><Intervention><Intervention Strategies><Intracellular Communication and Signaling><KI mice><Knock-in Mouse><Knock-out><Knockout><Leucine Zippers><Link><MAPK ERK Kinases><Mechanistic Target of Rapamycin><Mediating><Metabolic><Metabolic Processes><Metabolism><Microphthalmos><Modeling><Molecular><Molecular Target><Nutrient><Nutritional><Pathway interactions><Proteins><Proteomics><RAFT1><Reaction><Regulation><Research><Respiratory syncytial virus><Route><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Structure of germinal center of lymph node><Technology><Testing><Threonine/Tyrosine Protein Kinase><Transcription Factor Proto-Oncogene><Transcription factor genes><Viral Diseases><Viral Respiratory Tract Infection><Virus><Virus Diseases><Virus Replication><Wuhan coronavirus><activated B cells><airway immune response><amino acid metabolism><aminoacid><anti-flu><anti-influenza><antibody based therapies><antibody biosynthesis><antibody treatment><antibody-based immunity><antibody-based therapeutics><antibody-based treatment><antiflu><autophagy><biological signal transduction><coronavirus disease 2019><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><design><designing><developmental><dietary><extracellular signal related kinase><flu infection><flu virus infection><gain of function><guanosinetriphosphatase><hCoV19><host response><immune modulation><immune regulation><immune system response><immunoglobulin biosynthesis><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><in vivo><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><influenzavirus><interventional strategy><knockin mice><loss of function><mTOR><mammalian target of rapamycin><member><metabolism measurement><metabolomics><metabonomics><microphthalmia><mouse model><murine model><nCoV2><nanophthalmos><novel><nutritious><pathogen><pathway><respiratory><respiratory immune response><response><screening><screenings><sensor><transcription factor><viral infection><viral multiplication><viral replication><viral respiratory infection><virus infection><virus multiplication><virus-induced disease>